Diabetes is associated with higher cardiovascular morbidity and mortality. Hypertension, hyperlipidemia, and diabetes are independently associated with increased risk of cardiovascular disease. Subjects with Type 2 diabetes are at two- to four-fold increased risk of cardiovascular disease compared to those without diabetes.
Glucagon-like peptide-1 (GLP-1) is known as a pleiotropic peptide with metabolic and cardiovascular benefits. It is derived from pre-proglucagon, a 158 amino acid precursor polypeptide that is processed in different tissues to form a number of different proglucagon-derived peptides, including glucagon, glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) and oxyntomodulin (OXM), that are involved in a wide variety of physiological functions, including glucose homeostasis, insulin secretion, gastric emptying, and intestinal growth, as well as the regulation of food intake. GLP-1 is produced as a 37-amino acid peptide that corresponds to amino acids 72 through 108 of proglucagon (92 to 128 of preproglucagon). The predominant biologically active form is a 30-amino acid peptide hormone (GLP-1(7-37) acid) that is produced in the gut following a meal and rapidly degraded by an abundant endogenous protease-DPP4. Baggio, L. and Drucker, D., Gasteroenterology, 132:2131-2157 (2007).
GLP-1 and GLP-1 analogs, acting as agonists at the GLP-1 receptor, have been shown to be effective hypoglycemic control, e.g., type-2 diabetes. Certain GLP-1 analogs are being sold or are in development for treatment of type-2 diabetes including, e.g., liraglutide (Victoza® from Novo Nordisk), dulaglutide (Eli Lilly), Bydureon (AZ/BMS), Aliblutide (GSK) and Exenatide (Byetta® from Eli Lilly/Amylin).
One of the primary side effects following the initiation of GLP-1 therapy is gastrointestinal side effects, particularly nausea. This side effect is transient, resolves over time and can be mitigated by dose escalation. However, therapy is limited to patients that can tolerate the gastrointestinal side effects.
PCSK9 is a nonenzymatic target for LDL cholesterol reduction and PCSK9 mutations correlate with reductions in LDL cholesterol and coronary heart disease. Cohen J C, N Engl J Med, 354:1264 (2006). PCSK9 antibodies have been shown to reduce LDL cholesterol in statin-treated patients and multiple candidates are undergoing clinical review.
While there are a plurality of individual treatments for diabetes and cardiovascular diseases, there is a need for a single pharmaceutical composition to address both disease states (and the relationship between diabetes and cardiovascular disease). Providing a single pharmaceutical compound that has dual activities will reduce side effects, difficulties with patient compliance, and will increase beneficial outcomes to individual patients and will decrease costs incurred by the health care system.